Identification and analysis of the genes responsible for inherited neurodegenerative disorders

鉴定和分析导致遗传性神经退行性疾病的基因

基本信息

  • 批准号:
    09470041
  • 负责人:
  • 金额:
    $ 8.51万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    1997
  • 资助国家:
    日本
  • 起止时间:
    1997 至 1998
  • 项目状态:
    已结题

项目摘要

A novel class of inherited human neurodegenerations is now known to be caused by expanded CAG repeats encoding polyglutamines. Polyglutamine-containing protein fragments have been shown to accumulate as aggregates in the nucleus and in the cytoplasm, and to induce cell death when expressed in cultured cells, leading to the proposal that polyglutamine aggregation is an important step in the pathogenesis. Supportingly, nuclear inclusions containing expanded polyglutamines have been identified in neurons from patient brains and in neurons from transgenic mouse models of this class of neural disorders.We analyzed the consequence of polyglutamine expression in PC12 neuronal cells. Activated SEK1 accumulated with nuclear but not cytoplasmic polyglutamine aggregations, which consequently triggers cell death. Cell death induced by polyglutamine expression was inhibited by a dominant-negative SEK1(DN-SEK1), but not by DN-SEKI tagged with a nuclear export signal. Steady state SEKI expression itself was enhanced by two to three fold. Nuclearly aggregated polyglutamines, which were identified in PML bodies, colocalized with not only activated SEKl but also activated c-Jun. We also observed that nuclear inclusion-positive neurons from Huntington disease brains expressed SEK 1.This study provides molecular links between neurodegeneration observed in polyglutamine diseases, cell death signalling kinase cascades, and nuclear subdomains related to cell death. We propose that the nuclear PML bodies containing polyglutamine aggregates activate the SEK1-JNK kinase cascade, resulting in transduction of a death signal.
一类新的遗传性人类神经变性现在已知是由编码多谷氨酰胺的CAG重复扩增引起的。含有聚谷氨酰胺的蛋白片段在细胞核和细胞质中聚集,并在培养细胞中表达时诱导细胞死亡,因此提出聚谷氨酰胺聚集是发病机制的重要步骤。支持这一观点的是,在患者大脑的神经元和这类神经疾病的转基因小鼠模型的神经元中发现了含有扩展的多谷氨酰胺的核内含物。我们分析了聚谷氨酰胺在PC12神经元细胞中的表达。活化的SEK1聚集在细胞核而不是细胞质聚谷氨酰胺聚集,从而引发细胞死亡。显性阴性SEK1(DN-SEK1)可抑制聚谷氨酰胺表达诱导的细胞死亡,而带有核输出信号标记的DN-SEKI则不能。稳态SEKI表达量本身提高了2 ~ 3倍。在PML小体中发现的核聚集的多谷氨酰胺不仅与活化的SEKl共定位,还与活化的c-Jun共定位。我们还观察到来自亨廷顿病大脑的核包涵阳性神经元表达sek1。这项研究提供了在多谷氨酰胺疾病中观察到的神经变性、细胞死亡信号激酶级联反应和与细胞死亡相关的核亚结构域之间的分子联系。我们提出含有聚谷氨酰胺聚集体的核PML小体激活SEK1-JNK激酶级联,导致死亡信号的转导。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Nakamoto,M.et al.: "A CAG/CGT expansion in the normal population." Nat.Genet.17. 385-386 (1997)
Nakamoto,M.et al.:“CAG/CGT 在正常人群中的扩展。”
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    0
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  • 通讯作者:
Imaizumi, M. et al.: "Mutations in the E-domain of RAR alpha portion of the PML/RAR alpha chimeric gene may confer clinical resistancc to all-trans retinoic acid in acute promyelocytic leukemia."BLOOD. 92. 374-382 (1998)
Imaizumi, M. 等人:“PML/RAR α 嵌合基因的 RAR α 部分 E 结构域中的突变可能会赋予急性早幼粒细胞白血病对全反式视黄酸的临床抵抗力。”BLOOD。
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    0
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Kokubun, M., et al.: "Apoptosis-mediated regulation of recombinant human granulocyte colony-stimulating factor production by genetically engineered fibroblasts." Gene Therapy. 5. 923-929 (1998)
Kokubun, M. 等人:“基因工程成纤维细胞对重组人粒细胞集落刺激因子产生的凋亡介导调节”。
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  • 影响因子:
    0
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  • 通讯作者:
Segawa, T. et al.: "Prostate-specific amplification of expanded polyglutamine expression: A novel approach for cancer gene therapy"Cancer Res.. 58. 2282-2287 (1998)
Sekawa, T. 等人:“扩展聚谷氨酰胺表达的前列腺特异性扩增:癌症基因治疗的新方法”Cancer Res.. 58. 2282-2287 (1998)
  • DOI:
  • 发表时间:
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  • 影响因子:
    0
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  • 通讯作者:
Nakamoto, M., et al.: "Genetic Instabilities and Hereditary Neurological Diseases." eds Wells, R.D.and Warren, S.T. (Academic Press), 829 (1998)
Nakamoto, M. 等人:“遗传不稳定性和遗传性神经系统疾病。”
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KAKIZUKA Akira其他文献

KAKIZUKA Akira的其他文献

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{{ truncateString('KAKIZUKA Akira', 18)}}的其他基金

Elucidation of novel functions of VCP, a major ATPase in the cell
阐明细胞中主要 ATP 酶 VCP 的新功能
  • 批准号:
    19H03435
  • 财政年份:
    2019
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Analyses on novel functions of VCP, a major ATPase in the cell
细胞中主要 ATP 酶 VCP 的新功能分析
  • 批准号:
    16H05151
  • 财政年份:
    2016
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Analyses of the function and regulation of VCP, a major ATPase in the cells
细胞中主要 ATP 酶 VCP 的功能和调节分析
  • 批准号:
    23249016
  • 财政年份:
    2011
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Mechanisms for the regulation of growth and cell death in cancer cells
癌细胞生长和细胞死亡的调节机制
  • 批准号:
    17014043
  • 财政年份:
    2005
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research on Priority Areas
Functional analyses of VCP protein in neuronal cell death
VCP蛋白在神经细胞死亡中的功能分析
  • 批准号:
    16390092
  • 财政年份:
    2004
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Molecular analyses of cell death and vacuole formation that are induced by abnormal protein accumulation
异常蛋白质积累诱导的细胞死亡和液泡形成的分子分析
  • 批准号:
    14370057
  • 财政年份:
    2002
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Molecular analysis on nqurodegeneration
核变性的分子分析
  • 批准号:
    11470046
  • 财政年份:
    1999
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
rho p21 in Neural Development and Plasticity
rho p21 在神经发育和可塑性中的作用
  • 批准号:
    07044248
  • 财政年份:
    1995
  • 资助金额:
    $ 8.51万
  • 项目类别:
    Grant-in-Aid for international Scientific Research

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  • 批准号:
    10668769
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    2023
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    $ 8.51万
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    2023
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降低突变亨廷顿蛋白作为亨廷顿病潜在疗法的小分子的表征
  • 批准号:
    10759097
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    2023
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Brain-targeted delivery of therapeutic molecules by exosomes derived from engineered human iPS cells: a potential therapeutic approach for Huntington's disease
通过源自工程化人类 iPS 细胞的外泌体向大脑靶向递送治疗分子:亨廷顿病的潜在治疗方法
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    10588392
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    2023
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Ataxin2 和 Matrin3 在神经退行性疾病中的研究
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HIV-1 先天免疫感应的决定因素及其在塑造淋巴环境中的作用。
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    2023
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亨廷顿相关蛋白 40 在亨廷顿功能和亨廷顿病发病机制中的作用
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    10642313
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通过强制解开有毒 RNA 导致神经退行性变的分子起源
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